Leukopenia refers to an abnormal decrease in the
number of leukocytes. This may be secondary to a deficiency
of any or all of the WBCs but it is most commonly caused by
a depression of neutrophils (neutropenia).
Granulocytopenia, often used as a synonym for
neutropenia, technically refers to decreased eosinophils and
basophils as well as neutrophils.
Neutropenia is defined as less than 1.5 x
109 /L neutrophils in the perpherial blood. Fewer
than 1.0 x 10 /L neutrophils compromises the ability to
Agranulocytosis refers to extremely low levels of
neutrophils (< 0.5 x 109 /L).
The causes of leukopenia may be marrow failure,
peripheral destruction or shift into the storage or
Causes of decreased marrow production:
1) drug induction - ie. cytolytic; metabolic;
2) aplastic anemia - hypoplasia of bone marrow
3) myelofibrosis - metastatic cancer; granulomas;
4) ineffective hematopoiesis - ie. megaloblastic anemia
Decreased survival of neutrophils (increased utilization
or increased destruction):
This differs from marrow failure because of normal
numbers of erythroid and megakaryocytic elements. There will
often be myeloid hyperplasia, but without maturing
metamyelocyte, band, and polylobed forms.
Several minor causes of neutropenia need to be mentioned
in the category of "you can't diagnose what you don't know
Cyclic neutropenia is an autosomal dominant
disorder of unknown etiology in which 3-6 days of
neutropenia occur every 21-30 days in a periodic pattern.
During the periods of neutropenia the patient may develop
fever and infections such as stomatitis, cellulitis, and
vaginitis. There appears to be some abnormality of feedback
Chronic idiopathic neutropenia is a disorder in
which the neutrophil count is less than 1.0 x
109/L, but results in few infections.
A 35-year-old woman, with a history of depression x1
month was treated with phenothiazine by Dr. Lucy van Pelt.
She now presents with a 10 day history of fever, chills, and
malaise. In the past 3 days she noted increased weakness and
fatigability. The chest X-ray shows evidence of early
pneumonia. There is no splenomegaly. Laboratory values are
shown at right. The PB smear showed normocytic/ normochromic
What is your diagnosis?
What is the most likely cause?
A. ineffective erythropoiesis
B. accelerated destruction of neutrophils
C. drug induced
D. shift from circulating pool to marginal
E. aplastic anemia
Your second patient is a 27-year-old man in for an
insurance physical exam. He is pale and gave a history of
bleeding gums and several recent episodes of epitaxis. Upon
further questioning you find that he comes home from work
and goes almost immediately to bed. The CBC results you
ordered returned later that day and are shown at right. The
PB smear showed normocytic/hypochromic RBCs.
Calculate the absolute neutrophil count.
What is your diagnosis?
A. aplastic anemia
B. drug induced
C. accelerated destruction of neutrophils
Four mechanisms of drug-induced neutropenia:
Some drugs induce cytolysis causing general
marrow depression and resulting in aplastic anemia.
Examples include alkylating agents, inhibitors of
mitosis, DNA depolymerizors, and ionizing radiation.
DNA synthesis may be impaired by some drugs -
phenothazines, chloramphenicol, and purine and pyrimidine
antagonists (methotrexate, hydroxyurea, azothioprine,
cytosine arabinoside, and 6-mercaptopurine).
Ideiosyncratic reactions are seen with other
compounds (chloramphenicol, gold salts, phenylbutazone,
thiazides, sulfonamides, quinine, procanamide,
In immunologic neutropenia, the drug and neutrophil
surface protein form an antigenic complex. Antibody is
produced against against this complex and remains
inactive in the plasma. When this drug is given it
interacts with neutrophil surface protein and complexes
antibody. This causes leukoagglutiation or activation of
The neutrophils are destroyed by complement or the
clumps of neutrophils (at right) are removed from
the circulation or sequestered in the lungs, spleen, etc.
(seen with aminopyrine, thiouracil and some
Clinical features of neutropenia:
Fever may be secondary to the release of
leukokines during peripheral destruction of neutrophils.
The initial symptoms of neutropenia begin after
1-3 days with malaise, chills, sore throat, fever. Later
easy fatigability and weakness are seen.
Infection is the most serious consequence of neutropenia.
Neutropenia less than 1.0 x 10 9/L seriously
compromises the ability to fight infection. Agranulocytosis
(< 0.5 x 10 9 /L) may lead to death within
days due to overwhelming infection.
Other forms of leukopenia:
Eosinopenia*( < 0.04 x10 9 /L ) may
be seen in acute stress (glucocorticoid or epinephrine
stimulation), acute inflammation (interleukin-5), Cushing's
syndrome or corticosteroid administration.
Basopenia*( < 0.01 x10 9 /L ) may be
seen with corticosteroid administration, stress, acute
inflammation, and hyperthyroidism.
Monocytopenia ( < 0.2 x10 9 /L ) may
be seen in the first few hours after giving predisone, but
by 12 hours returns to normal.
Lymphocytopenia ( < 1.5 x10 9 /L for
adults; < 3.0 x10 9 /L for children ) may be
seen with corticosteroid Rx, chemoRx, irradiation, Hodgkin's
disease, HIV**infection, and chronic diseases ie. sarcoid,
*Note: Both eosinophils and basophils, like neutrophils,
exhibit diurnal variation, being lowest in the morning and
highest in the evening.
**Note: In HIV infection the lymphopenia is largely due
to a loss of CD4 positive T-helper lymphocytes.
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